1. Field of the Invention
The current invention concerns a process for manufacturing bulk solutions and lyophilized pure α-aztreonam lysinate for preparation of inhalable formulations for treatment of pulmonary bacterial infections caused by gram negative bacteria. In particular, the invention concerns a manufacturing process for preparation of pure α-aztreonam lysinate without need for conversion to β-aztreonam. The process is fast, safe, practical and economical.
The pure α-aztreonam lysinate bulk solution is easily converted into a lyophilized form. The lyophilized α-aztreonam lysinate is delivered to the lung as an aerosol or as an inhalable dry powder. For aerosolization, about 75 mg/ml of lyophilized α-aztreonam lysinate is reconstituted in about 1 to about 5 ml of normal or diluted saline or another aqueous solution of pH between 4.5 and 7.5, delivered to the lung endobronchial space in an aerosol having mass medium average diameter particles predominantly between 1 to 5μ using a nebulizer able to atomize the α-aztreonam lysinate solution into particles of required sizes.
For delivery of dry inhalable powder, α-aztreonam lysinate is lyophilized, milled or spray dried to particle sizes between about 1 and 5μ. Both the dry powder formulation or a reconstituted lyophilized α-aztreonam lysinate solid for aerosolization have a long shelf-life and storage stability.
2. Background and Related Disclosures
A wide variety of gram-negative bacteria cause severe pulmonary infections. Many of these bacteria are or become resistant to commonly used or specialty antibiotics and require treatment with new types of antibiotics.
Aztreonam is a synthetic antibiotic which has a good biological activity against gram-negative bacteria and its arginine salt derived from the β-aztreonam has previously been used for intravenous treatment of bacterial infections. However, its use is severely limited due to its low efficacy requiring administration of very large intravenous doses ranging from 1000 to 4000 mg a day.
Aztreonam is currently commercially available only as an arginine salt. Arginine has been shown to be toxic to the lung and causes lung tissue irritation, inflammation, bronchospasm and cough and therefore is not suitable for a delivery by aerosolization. Consequently, aztreonam arginine salt is not approved for inhalation use in the United States or elsewhere. Moreover, the β-aztreonam form used for preparation of aztreonam arginine is not stable and requires special handling conditions. Thus, although aztreonam would be an antibiotic of choice for complementary treatment of patients treated with tobramycin or other antibiotics, such treatment is not practical because of the high doses required and complications encountered with the β-aztreonam arginine salt.
However, aztreonam could become a drug of choice for inhalation treatment, if it could be prepared as a different salt than arginine, if such salt would be suitable for inhalation and if the aztreonam form would permit manufacturing of bulk solutions and salt conversion without raising the impurity levels.
Suitability of aztreonam for treatment of gram-negative bacterial infections by inhalation is disclosed in the U.S. Pat. No. 6,660,249 issued on Dec. 9, 2003 and the preferable aztreonam salt, namely α-aztreonam lysinate, even better suited for such purposes, is disclosed in a co-pending patent application Ser. No. 10/613,639, filed on Jul. 3, 2003, both by inventors. Both the U.S. Pat. No. 6,660,249 and the patent application Ser. No. 10,613,639 are hereby incorporated by reference in their entirety.
Thus it would be advantageous and desirable to provide a pure aztreonam salt which would be easier to manufacture and handle when an inhalable aztreonam formulation for delivery of aztreonam by aerosol or a dry powder is prepared.
It is, therefore, a primary object of this invention to provide a manufacturing process for preparation of a pure α-aztreonam lysinate without need for conversion of aztreonam into β-aztreonam, said pure α-aztreonam lysinate being suitable for delivery of aztreonam by inhalation into lungs for treatment of pulmonary gram-negative infections.
All patents, patent applications and publications cited herein are hereby incorporated by reference.